期刊
JOURNAL OF NUCLEAR MEDICINE
卷 57, 期 6, 页码 936-942出版社
SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.115.168906
关键词
gold nanoparticles; Lu-177; epidermal growth factor receptor (EGFR); locally advanced breast cancer; brachytherapy
资金
- Canadian Breast Cancer Foundation (Ontario Region)
- Natural Sciences and Engineering Research Council
- Ontario Graduate Scholarship (OGS)
- Terry Fox Foundation Excellence in Radiation Research
- Pharmaceutical Sciences Graduate Student Association Fellowship
Improvements in the treatment of locally advanced breast cancer (LABC) are needed. Our objective was to study a radiation nano medicine (gold nanoseeds) composed of 30-nm gold nanoparticles (AuNP) modified with polyethyleneglycol (PEG) chains linked to DOTA for complexing the beta-particle emitter Lu-177 and to panitumumab for targeting epidermal growth factor receptors (EGFR) (Lu-177-T-AuNP) as a novel neoadjuvant brachytherapy for LABC. Nontargeted gold nanoseeds (Lu-177-NT-AuNP) were constructed without panitumumab for comparison. Methods: Lu-177-T-AuNP or Lu-177-NT-AuNP was injected intratumorally in CD-1 athymic mice bearing subcutaneous EGFR-positive MDA-MB-468 human breast cancer tumors. Biodistribution and small-animal SPECT/CT imaging studies were performed to evaluate tumor and normal organ localization. A short-term (15 d) study was conducted to select the most effective amount of Lu-177-T-AuNP or Lu-177-NT-AuNP for treatment with long-term observation (90-120 d). Normal organ toxicities were assessed by monitoring body weight, blood cell counts, and serum alanine aminotransferase and creatinine. Radiation-absorbed doses in the tumor and normal organs were estimated by Monte Carlo N-Particle version 5.0 modeling. Results: Tumor radioactivity concentrations were high at 1 h after injection (>300-400 percentage injected dose per gram [%lD/g]) but decreased by 2-3-fold at 48 h after injection. Normal organ uptake was low (<0.5 %ID/g) except for the liver and spleen (<3 %ID/g), increasing by 2-5-fold at 48 h after injection. Treatment with 4.5 MBq (6 x 10(11) AuNP) of Lu-177-T-AuNP or Lu-177-NT-AuNP arrested tumor growth over 90 d without normal organ toxicity, whereas tumors continued to grow in mice treated with unlabeled T-AuNP or Lu-177-labeled PEG polymer not linked to AuNP. Survival was prolonged up to 120 d in mice treated with Lu-177-T-AuNP or Lu-177-NTAuNP. Radiation-absorbed doses to the tumor were 30 and 22 Gy for Lu-177-T-AuNP and Lu-177-NT-AuNP, respectively. Some tumor regions received high radiation doses (250-1,300 Gy). Normal organ doses were low (0.04-0.6 Gy). Conclusion: Gold nanoseeds injected intratumorally were highly effective for inhibiting the growth of breast cancer tumors in CD-1 athymic mice and caused no normal organ toxicity. These results are promising for their application for neoadjuvant brachytherapy of LABC. Because EGFR targeting was not required, the approach is broadly applicable to LABC with different phenotypes.
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